Cachexia in heart disease: highlights from the ESC 2010

Abstract

Cardiac cachexia is a co-morbidity that may develop in terminal stages of chronic heart failure (CHF). Up to 15% of ambulatory patients with heart failure are affected. Over the last decades, cardiac cachexia and alterations in muscle metabolism in heart disease have received increasing research interest. This article highlights some recent studies of cardiac cachexia that were presented at the annual meeting of the European Society of Cardiology in September 2010 in Stockholm, Sweden. Studies presented here were focused on effects of exercise training and protein degradation, particularly into the role of the ubiquitin-proteasome complex and its ubiquitin ligases MuRF-1 and MAFbx. Exercise training in patients with CHF was found to increase maximal oxygen consumption and to reduce MuRF-1 expression. Lysosomal muscle degradation does not seem to play a major role in patients with CHF, however, inflammatory cytokines such as tumor necrosis factor-a trigger muscle protein degradation. Other studies found that the serum levels of the adipokine adiponectin are elevated in patients with CHF and that these levels may be correlated with muscle mass, muscle strength in the arms, or with trunk fat mass. Another study showed that the expression of myostatin in skeletal muscle, a negative regulator of muscle growth that is essential for normal regulation of muscle mass, is decreased in spontaneously hypertensive rats with heart failure compared with control animals. This is also true for follistatin, a powerful antagonist, and its potential as a biomarker of muscle wasting. These findings may pave the way for effective treatment approaches to cardiac cachexia.

Fig. 1

Protein degradation by the ubiquitin–proteasome system: TNFα stimulation leads to protein degradation by the ubiquitin–proteasome complex and activation of NF–κB. Phosphorylation of IκB activates NF–κB. IκB and the proteins to be degraded are marked by a poly-ubiquitin chain. After ubiquitination, marked proteins and IκB are degraded by the proteasome complex. NF–κB can then signal into the nucleus, and transcription of the affiliated gene is induced

Fig. 2

Myostatin pathway: myostatin levels regulate skeletal muscle cell homeostasis. Myostatin is synthesized and secreted by muscle cell; it signals through the activin receptor IIB/ALK4/5 heterodimer to activate different pathways including Smad2/3 and MAPK (ERK1/2, p38MAPK) resulting in the regulation of gene expression. Myostatin stimulation results in inhibition of muscle growth and muscle differentiation